Composition for treating or preventing glomerulopathy

ABSTRACT

A composition for treating or preventing glomerulopathy which contains a compound of the formula (I): 
                 
 
wherein, for example,
     R 1  and R 2  are each independently hydrogen atom, optionally substituted lower alkyl, optionally substituted aralkyl, etc.;   R 3  is 1,4-phenylene and 2,5-thiophendiyl;   R 4  is the substituents represented by the formula, etc.: 
                 
 
wherein
   R 5  is hydrogen atom, optionally substituted amino, etc.; and   Y is NHOH or OH, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

TECHNICAL FIELD

This invention relates to a composition for treating or preventingglomerulopathy, especially glomerulonephritis and diabetic nephropathy,having a superior antiproteinuric effect and to a novel compound havingsuperior inhibitory activity for type IV collagenase and anantiproteinuric effect and a composition containing it for treating orpreventing.

BACKGROUND ART

A glomerulus is organized by epithelial cells, mesangial cells,endothelial cells, and epithelial cells of Bowman's capsule. Theglomerulus filtrates blood to produce a glomerular filtrate containingsubstantially the same components as plasma components of whichmolecular weight is 10,000 or less. Generally, the filtration iscontrolled not to leak essential substances in blood, especially serumprotein, to urine.

Glomerulus damage causes the growth of mesangial cells which are one ofthe glomerulus component cells and the expansion of a neighborextracellular matrix to increase the amount of urinary proteinexcretion. It is known that the increase of urinary protein excretionfurther lowers the renal function by leading glomerulopathy to damage ofrenal tubules. Therefore, the inhibition of the urinary proteinexcretion is expected to improve various diseases associated withglomerulopathy. Such damage is derived from not only a primary diseasebut also a systemic disease such as diabetes. However, initiation andprogression mechanisms remain uncertain and a fundamental method fortreatment is not established.

As the present treating method, symptomatic therapies are carried out,but they have many problems. For example, the immunosuppressants areused for patients of nephritis because many types of nephritis areconsidered to be caused by immunologic mechanism, but nephrotoxicityoccurs by the prolonged administration. Though steroids are alsoadministered to the patients of nephritis, some nephritis are resistantto them. Recently, it is proved that angiotensin converting enzymeinhibitors (antihypertensive agents) are useful for nephritis. However,the medicament for nephritis without a hypotensive effect is required.

Accordingly, pharmacotherapy of glomerulopathy has been in a trial anderror stage. The treatment of glomerulopathy is made more difficult bythe fact that the cause of glomerulopathy is not all alike and clinicalcourse full of variety can not easily be prospected.

As a treating agent for nephritis other than the above mentionedmedicament, compounds described in JP-A-9-87176 are exemplified.

Compounds similar to those of the present invention are described inWO97/27174, EP0757984 A1, EP0757037 A2, WO97/45402, WO97/44315,WO96/00214, WO95/35276, and WO97/05865.

DISCLOSURE OF INVENTION

In the above situation, the inventors of the present invention havestudied on the medicament which can inhibit the initiation andprogression of glomerulopathy such as glomerulonephritis and diabeticnephropathy or decrease urinary protein excretion.

The inventors of the present invention made glomerulopathy model ratswhich leak urine proteins by using a nephritogenic antibody and searchedfor compounds inhibiting the initiation and progression of the damage ofmodel rats. In result, the inventors of the present invention found thatsome sulfonamide derivatives inhibited the initiation and progression ofglomerulopathy, especially glomerulonephritis and diabetic nephropathythrough the inhibition of protein excretion and they are useful treatingor preventing them.

The present invention relates to i) to xxxiv) represented below.

-   i) A composition for treating or preventing glomerulopathy which    contains a compound of the formula (I):    wherein R¹ and R² are each independently hydrogen atom, optionally    substituted lower alkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heteroaryl, or    optionally substituted heteroarylalkyl;-   R³ is 1,4-phenylene or 2,5-thiophendiyl;-   R⁴ is a substituent represented by the formula:    wherein R⁵ is hydrogen atom, hydroxy, optionally substituted lower    alkyloxy, mercapto, lower alkylthio, cycloalkyl, halogen, carboxy,    lower alkyloxycarbonyl, nitro, cyano, lower holoalkyl, aryloxy,    optionally substituted amino, guanidino, optionally substituted    lower alkyl, lower alkenyl, lower alkynyl, acyl, acyloxy,    —CONR^(A)R^(B), —N(R^(C))COR^(D) (wherein R^(A), R^(B), and R^(C)    are the same or different selected from hydrogen atom, lower alkyl,    or aralkyl; R^(D) is lower alkyl, aryl, and aralkyl), optionally    substituted non-aromatic heterocyclic group, or optionally    substituted heteroaryl;-   R⁶ is optionally substituted lower alkyl, cycloalkyl, lower    alkyloxy, halogen, lower alkylthio, optionally substituted amino,    carboxy, lower alkyloxycarbonyl, aryloxy, phenyl optionally    substituted non-aromatic heterocyclic group, or optionally    substituted heteroaryl; and-   Y is NHOH or OH, its optically active substance, their    pharmaceutically acceptable salt, or hydrate thereof.-   ii) A composition for treating or preventing glomerulopathy which    contains a compound of the formula (II):    wherein R¹, R², and R³ are as defined above;-   R⁷ is a substitution represented by the formula:    wherein R⁸ is hydrogen atom, hydroxy, lower alkyloxy, mercapto,    lower alkylthio, cycloalkyl, halogen, carboxy, lower    alkyloxycarbonyl, nitro, cyano, lower haloalkyl, aryloxy, optionally    substituted amino, guanidino, optionally substituted lower alkyl,    lower alkenyl, lower alkynyl, alkanoyl, acyloxy, or optionally    substituted heteroaryl;-   R⁹ is optionally substituted lower alkyl, cycloalkyl, carboxy, lower    alkyloxycarbonyl, aryloxy, or phenyl; and-   Y is NHOH or OH, its optically active substance, their    pharmaceutically acceptable salt, or hydrate thereof.-   iii) A composition for treating or preventing glomerulopathy which    contains a compound of the formula (I):    wherein R¹, R², and R³ are as defined above;-   R⁴ is a substituent represented by the formula:    wherein R¹⁰ is hydrogen atom, optionally substituted lower alkyloxy,    lower alkylthio, halogen, optionally substituted amino, optionally    substituted lower alkyl, or optionally substituted non-aromatic    heterocyclic group;-   R¹¹ is optionally substituted lower alkyl, lower alkylthio, halogen,    optionally substituted amino, phenyl, optionally substituted    non-aromatic heterocyclic group, or optionally substituted    heteroaryl; and-   Y is NHOH or OH, its optically active substance, their    pharmaceutically acceptable salt, or hydrate thereof.-   iv) A composition for treating or preventing glomerulopathy which    contains a compound of the formula (II):    wherein R¹, R², and R³ are as defined above;-   R⁷ is a substituent represented by the formula:    wherein R¹² is hydrogen atom, halogen, nitro, optionally substituted    lower alkyl lower alkyloxy, or lower alkylthio;-   R¹³ is optionally substituted lower alkyl or phenyl; and-   Y is NHOH or OH, its optically active substance, their    pharmaceutically acceptable set, or hydrate thereof.-   v) A composition for treating or preventing glomerulopathy which    contains a compound of the formula (III):    wherein R¹, R¹⁰, and Y are as defined above; and R¹⁴ is hydrogen    atom or lower alkyl, its optically active substance, their    pharmaceutically acceptable salt, or hydrate thereof.-   vi) A composition for treating or preventing glomerulopathy which    contains a compound of the formula (IV):    wherein R¹, R¹², R¹⁴, and Y are as defined above, its optically    active substance, their pharmaceutically acceptable salt, or hydrate    thereof.-   vii) A composition for treating or preventing glomerulopathy which    contains a compound of the formula (V):    wherein R¹, R¹⁰, R¹⁴, and Y are as defined above, its optically    active substance, their pharmaceutically acceptable salt, or hydrate    thereof.-   viii) A composition for treating or preventing glomerulopathy which    contains a compound of the formula (VI):    wherein R¹, R¹², R¹⁴, and Y are as defined above, its optically    active substance, their pharmaceutically acceptable salt, or hydrate    thereof.-   ix) A composition for treating or preventing glomerulopathy which    contains a compound of the formula (VII):    wherein R¹, R¹⁰, R¹⁴, and Y are as defined above, its optically    active substance, their pharmaceutically acceptable salt, or hydrate    thereof.-   x) A composition for treating or preventing glomerulopathy which    contains a compound of the formula (VIII):    wherein R¹, R¹², R¹⁴, and Y are as defined above, its optically    active substance, their pharmaceutically acceptable salt, or hydrate    thereof.-   xi) A composition for treating or preventing glomerulopathy which    contains a compound of the formula (IX):    wherein R¹, R¹⁰, R¹⁴, and Y are as defined above, its optically    active substance, their pharmaceutically acceptable salt, or hydrate    thereof.-   xii) A composition for treating or preventing glomerulopathy which    contains a compound of the formula (X):    wherein R¹, R¹², R¹⁴, and Y are as defined above, its optically    active substance, their pharmaceutically acceptable salt, or hydrate    thereof.-   xiii) A composition for treating or preventing glomerulopathy which    contains a compound of the formula (XI):    wherein R¹, R¹⁰, R¹⁴, and Y are as defined above, its optically    active substance, their pharmaceutically acceptable salt, or hydrate    thereof.-   xiv) A composition for treating or preventing glomerulopathy which    contains a compound of the formula (XII):    wherein R¹, R¹², R¹⁴, and Y are as defined above, its optically    active substance, their pharmaceutically acceptable salt, or hydrate    thereof.-   xv) A composition for treating or preventing glomerulopathy which    contains a compound of the formula (XII):    wherein R¹, R¹⁰, R¹⁴, and Y are as defined above, its optically    active substance, their pharmaceutically acceptable salt, or hydrate    thereof. p0 xvi) A composition for treating or preventing    glomerulopathy which contains a compound of the formula (XIV):    wherein R¹, R¹², R¹⁴, and Y are as defined above, its optically    active substance, their pharmaceutically acceptable salt, or hydrate    thereof.-   xvii) A composition for treating or preventing glomerulopathy which    contains a compound of the formula (XV):    wherein R¹, R¹¹, R¹⁴, and Y are as defined above, its optically    active substance, their pharmaceutically acceptable salt, or hydrate    thereof.-   xviii) A composition for treating or preventing glomerulopathy which    contains a compound of the formula (XVI):    wherein R¹, R¹³, R¹⁴, and Y are as defined above, its optically    active substance, their pharmaceutically acceptable salt, or hydrate    thereof.-   xix) The composition for treating or preventing glomerulopathy of    any one of above i) to xviii), wherein R¹ is hydrogen atom, methyl,    i-propyl, i-butyl, optionally substituted benzyl, optionally    substituted indol-3-ylmethyl, or phenylaminocarbonylethyl.-   xx) The composition for treating or preventing glomerulopathy of any    one of above i) to xviii), wherein R¹ is i-propyl, benzyl, or    indol-3-ylmethyl.-   xxi) The composition for treating or preventing glomerulopathy of    any one of above i) to xx), wherein R² and R¹⁴ are hydrogen atom.-   xxii) The composition for treating or preventing glomerulopathy of    any one of above i) to xxi), wherein Y is OH.-   xxiii) The composition for treating or preventing glomerulopathy of    any one of above i) to xxii), wherein glomerulopathy is    glomerulonephritis.-   xxiv) The composition for treating or preventing glomerulopathy of    any one of above i) to xxii), wherein glomerulopathy is diabetic    nephropathy.-   xxv) A compound of the formula (XVII):    wherein R¹, R¹⁰, R¹⁴, and Y are as defined above, its optically    active substance, their pharmaceutically acceptable salt, or hydrate    thereof.-   xxvi) A compound of the formula (XVIII):    wherein R¹, R¹⁰, R¹⁴, and Y are as defined above, its optically    active substance, their pharmaceutically acceptable salt, or hydrate    thereof.-   xxvii) A compound of the formula (XIX):    wherein R¹, R¹⁰, R¹⁴, and Y are as defined above, its optically    active substance, their pharmaceutically acceptable salt, or hydrate    thereof.-   xxviii) A compound of the formula (XX):    wherein R¹, R¹⁰, R¹⁴, and Y are as defined above, its optically    active substance, their pharmaceutically acceptable salt, or hydrate    thereof.-   xxix) A compound of the formula (XXI):    wherein R¹, R¹⁰, R¹⁴, and Y are as defined above, its optically    active substance, their pharmaceutically acceptable salt, or hydrate    thereof.-   xxx) A compound of the formula (XXII):    wherein R¹, R¹⁰, R¹⁴, and Y are as defined above, its optically    active substance, their pharmaceutically acceptable salt, or hydrate    thereof.-   xxxi) A compound of the formula (XXIII):    wherein R¹, R¹⁰, R¹⁴, and Y are as defined above, its optically    active substance, their pharmaceutically acceptable salt, or hydrate    thereof.-   xxxii) A pharmaceutical composition containing a compound of any one    of above xxv to xxxi).-   xxxiii) A composition for inhibiting matrix metalloproteinase    containing a compound of any one of above xxv) to xxxi).-   xxxiv) A composition for inhibiting type IV collagenase containing a    compound of any one of above xxv) to xxxi).-   xxxv) A composition for treating or preventing glomerulopathy which    contains a compound of any one of above xxv) to xxxi).-   xxxvi) A composition for treating or preventing glomerulopathy which    contains a compound of the formula (XXIV):    wherein the combination of each substituent is represented below,    its optically active substance, their pharmaceutically acceptable    salt, or hydrate thereof.

TABLE 1 Compound No. Y R¹ R² R¹⁵ 1 NHOH (CH₃)₂CH— H

2 NHOH (CH₃)₂CH— Me

3 OH

H

4 NHOH

H

5 OH (CH₃)₂CH— H

6 OH PhCH₂— H

7 OH (CH₃)₂CH— H

8 OH

H

9 NHOH (CH₃)₂CH— H

10 OH (CH₃)₂CH— H

11 OH (CH₃)₂CH— H

12 OH PhCH₂— H

13 OH (CH₃)₂CH— H

14 OH

H

15 OH (CH₃)₂CH— H

16 OH (CH₃)₂CH— H

17 OH PhCH₂— H

18 OH PhCH₂— H

19 OH CH₃— H

20 OH PhCH₂— H

21 OH PhCH₂— H

22 OH CH₃— H

23 OH PhCH₂— H

24 OH CH₃— H

25 OH (CH₃)₂CH— H

26 OH (CH₃)₂CH— H

27 OH (CH₃)₂CH— H

28 OH H H

29 OH H H

30 OH

H

31 OH (CH₃)₂CH— H

32 OH PhCH₂— H

33 NHOH PhCH₂— H

34 OH PhCH₂— H

35 OH

H

36 OH

H

37 OH

H

38 OH (CH₃)₂CH— H

39 OH (CH₃)₂CH— H

40 OH

H

41 OH PhCH₂— H

42 NHOH (CH₃)₂CH— H

43 OH PhCH₂— H

44 OH PhCH₂— H

45 OH (CH₃)₂CH— H

46 OH (CH₃)₂CH— H

47 OH (CH₃)₂CH— H

48 OH PhNHCO(CH₂)₂— H

49 OH PhCH₂— H

50 OH PhCH₂— H

51 OH (CH₃)₂CH— H

52 OH (CH₃)₂CHCH₂— H

53 OH (CH₃)₂CH— H

54 OH (CH₃)₂CH— H

55 OH (CH₃)₂CH— H

56 OH (CH₃)₂CH— H

57 OH CH₃— H

58 OH (CH₃)₂CH— H

59 OH MeS—CH₂CH₂— H

60 OH 4-OH—Ph— H

61 OH PhCH₂— H

62 OH PhCH₂— H

63 OH (CH₃)₂CH— H

64 OH (CH₃)₂CH— H

65 NHOH (CH₃)₂CH— H

66 OH PhCH₂— H

67 OH PhCH₂— H

68 OH

H

69 OH

H

70 NHOH

H

71 NHOH (CH₃)₂CH— H

72 NHOH

H

73 OH

H

74 OH (CH₃)₂CH— H

75 OH (CH₃)₂CH— H

76 OH

H

77 OH PhCH₂— H

78 OH

H

79 OH (CH₃)₂CH— H

80 NHOH

H

81 OH

H

82 OH

H

83 OH

H

84 OH (CH₃)₂CH— H

85 OH PhCH₂— H

86 OH

H

87 OH PhCH₂— H

88 OH

H

89 NHOH

H

90 OH

H

91 OH

H

92 OH

H

93 OH PhCH₂— H

94 OH PhCH₂— H

95 OH PhCH₂— H

96 OH (CH₃)₂CH— H

97 OH (CH₃)₂CH— H

98 OH (CH₃)₂CH— H

99 OH (CH₃)₂CH— H

100 OH (CH₃)₂CH— H

101 OH (CH₃)₂CH— H

102 OH (CH₃)₂CH— H

103 OH (CH₃)₂CH— H

104 OH (CH₃)₂CH— H

105 OH PhCH₂— H

106 OH (CH₃)₂CH— H

107 OH (CH₃)₂CH— H

108 OH PhCH₂— H

109 OH

H

110 OH PhCH₂— H

111 OH

H

112 OH (CH₃)₂CH— H

113 OH (CH₃)₂CHCH₂— H

114 OH CH₃— H

115 OH PhCH₂— H

116 OH H H

117 OH CH₃— H

118 OH (CH₃)₂CH— H

119 OH (CH₃)₂CH— H

120 OH (CH₃)₂CH— H

121 OH (CH₃)₂CH— H

-   xxxvii) A composition for treating or preventing glomerulopathy    which contains a compound of the formula (XXIV):    wherein the combination of each substituent is represented below,    its optically active substance, their pharmaceutically acceptable    salt, or hydrate thereof.

TABLE 2 Compound No. Y R¹ R² R¹⁵ 1 NHOH (CH₃)₂CH— H

2 NHOH (CH₃)₂CH— Me

3 OH

H

4 NHOH

H

5 OH (CH₃)₂CH— H

6 OH PhCH₂— H

7 OH (CH₃)₂CH— H

31 OH (CH₃)₂CH— H

32 OH PhCH₂— H

33 NHOH PhCH₂— H

34 OH PhCH₂— H

35 OH

H

36 OH

H

37 OH

H

38 OH (CH₃)₂CH— H

39 OH (CH₃)₂CH— H

63 OH (CH₃)₂CH— H

64 OH (CH₃)₂CH— H

65 NHOH (CH₃)₂CH— H

66 OH PhCH₂— H

67 OH PhCH₂— H

68 OH

H

69 OH

H

70 NHOH

H

71 NHOH (CH₃)₂CH— H

72 NHOH

H

88 OH

H

89 NHOH

H

90 OH

H

91 OH

H

92 OH

H

93 OH PhCH₂— H

94 OH PhCH₂— H

xxxviii) The composition for treating or preventing glomerulopathy ofany one of above xxxv) to xxxvii), wherein glomerulopathy isglomerulonephritis.

-   xxxix) The composition for treating or preventing glomerulopathy of    any one of above xxxv) to xxxvii), wherein glomerulopathy is    diabetic nephropathy.

Among the above mentioned compounds with superior activity for treatingor preventing glomerulopathy, preferred are shown below.

Compound No.: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18,19, 20, 21, 23, 24, 26, 28, 29, 31, 32, 33, 34, 35, 39, 40, 41, 44, 48,51, 52, 54, 55, 56, 57, 59, 61, 62, 73, 81, 82, 84, 86, 91, 92, 93, 94,95, 97, 98, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 112, 113,114, 115, 119, 120, and 121.

More preferred compounds are No.: 1, 2, 3, 4; 5, 6, 7, 9, 12, 13, 15,16, 17, 18, 19, 23, 29, 31, 32, 33, 34, 35, 39, 51, 54, 55, 56, 57, 59,61, 62, 80, 82, 84, 86, 91, 92, 93, 94, 95, 96, 97, 101, 108, 112, 113,115, 119, 120, and 121.

Most preferred compounds are No.: 1, 2, 4, 7, 9, 12, 15, 16, 17, 18, 19,23, 31, 33, 32, 34, 39, 54, 56, 57, 61, 62, 80, 84, 86, 91, 92, 95, 97,101, 108, and 121.

The term “glomerulopathy” herein used means dysfunction of glomerulus orchange of form of glomerulus caused by an endogenous or exogenousfactor.

The term “glomerulonephritis” herein used means renal dysfunctionderived from glomerulus dysfunction which is caused by a hereditary orexogenous factor or autoimmune disorder. This term includes nephrosissuch as membranous nephropathy without inflammatory response.

The term “diabetic nephropathy” herein used means all renal dysfunctionobserved after crisis of diabetes.

The term “lower alkyl” herein used means C₁ to C₆ straight or branchedchain alkyl, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like. C₁ toC₄ alkyl is preferred.

The term “cycloalkyl” herein used are exemplified by cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The term “aryl” herein used means monocyclic or condensed ring aromatichydrocarbons. Examples of the aryl are phenyl, 1-naphthyl, 2-naphthyl,and the like.

The term “aralkyl” herein used means the above mentioned “lower alkyl”substituted with the above mentioned “aryl” at any possible position.Examples of the aralkyl are benzyl, phenethyl (2-phenethyl),phenylpropyl (e.g., 3-phenylpropyl), naphthylmethyl (e.g.,1-naphthylmethyl and 2-naphthylmethyl), anthrylmethyl (e.g.,9-anthrylmethyl), and the like. Benzyl is preferred.

The term “heteroaryl” herein used means a 5 to 6 membered aromaticheterocyclic group which contains one or more hetero atoms selected fromthe group consisting of oxygen, sulfur, and nitrogen atoms in the ringand may be fused with the above mentioned “aryl”, “non-aromaticheterocyclic group”, and other “heteroaryl” at any possible position.Examples of the heteroaryl are pyrrolyl (e.g., 1-pyrrolyl), indolyl(e.g., 3-indolyl), carbazolyl (e.g., 3-carbazolyl), imidazolyl (e.g.,4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl), benzimidazolyl (e.g.,2-benzimidazolyl), indazolyl (e.g., 3-indazolyl), indolizinyl (e.g.,6-indolizinyl), pyridyl (e.g., 4-pyridyl), quinolyl (e.g., 5-quinolyl),isoquinolyl (e.g., 3-isoquinolyl), acridinyl (e.g., 1-acridinyl),phenanthridinyl (e.g., 2-phenanthridinyl), pyridazinyl (e.g.,3-pyridazinyl), pyrimidinyl (e.g., 4-pyrimidinyl), pyrazinyl (e.g.,2-pyrazinyl), cinnolinyl (e.g., 3-cinnolinyl), phthalazinyl (e.g.,2-phthalazinyl), quinazolinyl (e.g., 2-quinazolinyl), isoxazolyl (e.g.,3-isoxazolyl), benzisoxazolyl (e.g., 3-benzisoxazolyl), oxazolyl (e.g.,2-oxazolyl), benzoxazolyl (e.g., 2-benzoxazolyl), benzoxadiazolyl (e.g.,4-benzoxadiazolyl), isothiazolyl (e.g., 3-isothiazolyl),benzisothiazolyl (e.g., 2-benzisothiazolyl), thiazolyl (e.g.,2-thiazolyl), benzothiazolyl (e.g., 2-benzothiazolyl), furyl (e.g.,3-furyl), benzofuryl (e.g., 3-benzofuryl), thienyl (e.g., 2-thienyl),benzothienyl (e.g., 2-benzothienyl), tetrazolyl, and the like. Indolyl,pyrazolyl, and pyridyl are preferred.

The term “heteroarylalkyl” herein used means the above mentioned “loweralkyl” substituted with the above mentioned “heteroaryl” at any possibleposition. Examples of the heteroarylalkyl are thiazolylmethyl (e.g.,4-thiazolylmethyl), thiazolylethyl (e.g., 5-thiazolyl-2-ethyl),indolylmethyl (e.g.; indol-3-ylmethyl), imidazolylmethyl (e.g.,4-imidazolylmethyl), benzothiazolylmethyl (e.g.,2-benzothiazolylmethyl), benzopyrazolylmethyl (e.g.,1-benzopyrazolylmethyl), benzotriazolylmethyl (e.g.,4-benzotriazolylmethyl), benzoquinolylmethyl (e.g.,2-benzoquinolylmethyl), benzimidazolylmethyl (e.g.,2-benzimidazolylmethyl), pyridylmethyl (e.g., 2-pyridylmethyl), and thelike. As a preferred heteroarylalkyl, indol-3-ylmethyl is exemplified.

The term “non-aromatic heterocyclic group” herein used means a 5 to 7membered non-aromatic ring which contains one or more hetero atomsselected from the group consisting of oxygen, sulfur, and nitrogen atomsin the ring and condensed ring which are fused with two or morethemselves. Examples of the non-aromatic heterocyclic group arepyrrolidine, piperidine, piperazine, octahydroquinoline,tetrahydrofuran, tetrahydropyrane, morpholine, and the like. Pyrrolidineand morpholine are preferred.

The term “lower alkyloxy” herein used means alkyloxy of which alkyl partis the above mentioned lower alkyl. Examples of the lower alkyloxy aremethyloxy, ethyloxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy,sec-butyloxy, tert-butyloxy, and the like. C1 to C4 alkyloxy ispreferred.

The term “halogen” herein used means fluoro, chloro, bromo, and iodo.Fluoro, chloro, and bromo are preferred.

The term “lower alkylthio” herein used means alkylthio of which alkylpart is the above mentioned “lower alkyl”. Examples of the loweralkylthio are methylthio, ethylthio, and the like.

The term “lower alkyloxycarbonyl” herein used means loweralkyloxycarbonyl of which alkyloxy part is the above mentioned “loweralkyloxy”. Examples of the lower alkyloxycarbonyl are methyloxycarbonyl,ethyloxycarbonyl, n-propyloxycarbonyl, and the like.

The term “lower haloalkyl” herein used means the above mentioned “loweralkyl” which is substituted with the above mentioned “halogen” at 1 to 5positions. Examples of the lower haloalkyl are trichloromethyl,trichloroethyl, trifluoromethyl trifluoroethyl, and the like.

The term “aryloxy” herein used means aryloxy of which aryl part is theabove mentioned “aryl”. Examples of the aryloxy are phenyloxy and thelike.

The term “lower alkenyl” herein used means C₂ to C₆ straight or branchedchain alkenyl. Examples of the lower alkenyl are vinyl, allyl, propenyl,butenyl, and the like.

The term “lower alkynyl” herein used means C₂ to C₆ straight or branchedchain alkynyl. Examples of the lower alkynyl are ethynyl, 1-propynyl,propargyl, 1-hexynyl, and the like.

The term “acyl” herein used means alkanoyl of which carbonyl is bondedto the above mentioned “lower alkyl” or “cycloalkyl” and aroyl of whichcarbonyl is bonded to the above mentioned “aryl”. Examples of the acylare acetyl, n-propanoyl, isopropanoyl, n-butyloyl t-butyloyl,cyclopropanoyl, cyclobutanoyl, cyclopentanoyl, cyclohexanoyl benzoyl,and the like. Acetyl and benzoyl are preferred.

The term “alkanoyl” herein used means alkanoyl of which carbonyl isbonded to the above mentioned “lower alkyl” or “cycloalkyl”. Examples ofthe alkanoyl are acetyl, n-propanoyl, isopropanoyl, n-butyloyl,t-butyloyl, cyclopropanoyl, cyclobutanoyl, cyclopentanoyl,cyclohexanoyl, and the like. Acetyl is preferred.

The term “acyloxy” herein used means acyloxy of which oxygen atom isbonded directly to the above mentioned “acyl”. Examples of the acyloxyare acetyloxy, n-propanoyloxy, isopropanoyloxy, n-butyloyloxy,t-butyloyloxy, cyclopropanoyloxy, cyclobutanoyloxy, cyclopentanoyloxy,cyclohexanoyloxy, benzoyloxy, α-naphthoyloxy, β-naphthoyloxy, and thelike.

The term “optionally substituted amino” herein used means aminosubstituted with one, two, or more of the above mentioned “lower alkyl”,“aralkyl”, or “heteroarylalkyl” or non-substituted. Examples of theoptionally substituted amino are amino, methylamino, dimethylamino,ethylmethylamino, diethylamino, benzylamino, and the like.

The substituents of “optionally substituted alkyl” for R¹ and R² arehydroxy, alkyloxy (e.g., methyloxy and ethyloxy), mercapto; alkylthio(e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl), halogen (e.g., fluoro, chloro, bromo, andiodo), carboxy, lower alkyloxycarbonyl (e.g., methyloxycarbonyl andethyloxycarbonyl), nitro, cyano, lower haloalkyl (e.g.,trifluoromethyl), optionally substituted amino (e.g., methylamino,dimethylamino, and carbamoylamino), optionally substituted carbamoyl(e.g., phenylcarbamoyl), guanidino, phenyl, benzyloxy, and the like.These substituents are able to bind to it at one or more of any possiblepositions.

Examples of “optionally substituted alkyl” of R¹ and R² are methyl,ethyl, n-propyl, i-propyl, i-butyl, phenylcarbamoylethyl,methylthioethyl, and the like.

The substituents for “optionally substituted alkyl” of R⁵, R⁶, R¹², andR¹³ are optionally protected hydroxy (e.g., hydroxy, methylsulfonyloxy,and p-toluenesulfonyloxy), alkyloxy (e.g., methyloxy, ethyloxy,n-propyloxy, and n-butyloxy), azide, mercapto, alkylthio (e.g.,methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy,lower alkyloxycarbonyl (e.g., methyloxycarbonyl and ethyloxycarbonyl),nitro, cyano, lower haloalkyl (e.g., trifluoromethyl), optionallysubstituted amino (e.g., methylamino, dimethylamino, andcarbamoylamino), guanidino, phenyl benzyloxy, and the like. Thesesubstituents are able to bind to it at one or more of any possiblepositions. Preferred substituents are optionally protected hydroxy,azide, halogen, and optionally substituted amino.

Examples of “optionally substituted alkyl” of R⁵, R⁶, R¹², and R¹³ aremethyl, ethyl, n-propyl, i-propyl, n-butyl, hydroxymethyl,2-hydroxyethyl, 2-ehtylazide, trifluoromethyl, and the like.

The substituents for “optionally substituted alkyl” of R⁸, R⁹, R¹², andR¹³ are optionally protected hydroxy (e.g., hydroxy, methylsulfonyloxy,and p-toluenesulfonyloxy), alkyloxy (e.g., methyloxy and ethyloxy),azide, mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g.,fluoro, chloro, bromo, and iodo), carboxy, lower alkyloxycarbonyl (e.g.,methyloxycarbonyl and ethyloxycarbonyl), nitro, cyano, lower haloalkyl(e.g., trifluoromethyl), optionally substituted amino (e.g.,methylamino, dimethylamino, and carbamoylamino), guanidino, phenyl,benzyloxy, and the like. These substituents are able to bind to it atone or more of any possible positions. Preferred substituents areoptionally protected hydroxy, azide, halogen, and optionally substitutedamino.

Examples of the substituents of “optionally substituted alkyloxy” hereinused are optionally substituted amino (amino, methylamino,dimethylamino, ethylamino, ethylmethylamino, and diethylamino), and thelike. Preferred is optionally substituted amino.

Examples of “optionally substituted alkyloxy” are methyloxy, ethyloxy,n-propyloxy, n-butyloxy, 3-dimethylaminopropyloxy, and the like.

Substituents on the aromatic ring of “optionally substituted aryl”,“optionally substituted aralkyl”, “optionally substituted heteroaryl”,and “optionally substituted heteroarylalkyl” are, for example, hydroxy,lower alkoxy (e.g., methyloxy and ethyloxy), mercapto, lower alkylthio(e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, andcyclopentyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy,lower alkyloxycarbonyl (e.g., methyloxycarbonyl and ethyloxycarbonyl),nitro, cyano, lower haloalkyl (e.g., trifluoromethyl), aryloxy (e.g.,phenyloxy), optionally substituted amino (e.g., methylamino,dimethylamino, diethylamino, and benzylidenamino), guanidino, loweralkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, tert-butyl, n-pentyl, i-pentyl, neo-pentyl, and tert-pentyl),lower alkenyl (e.g., vinyl and propenyl), alkynyl (e.g., ethynyl andphenylethynyl), lower alkanoyl (e.g., formyl, acetyl, and propionyl),acyloxy (e.g., acetyloxy), acylamino, lower alkylsulfonyl (e.g.,methylsulfonyl), phenyl, benzyl, an azo group (e.g., phenylazo),optionally substituted heteroaryl (e.g., 3-pyridyl), optionallysubstituted ureido (e.g., ureido and phenylureido), and the like. Thesesubstituents are able to bind to it at one or more of any possiblepositions.

The examples of the substituents for “optionally substitutednon-aromatic heterocyclic group” are lower alkyl (e.g., methyl ethyln-propyl, and i-propyl) and the like.

The examples of “optionally substituted non-aromatic heterocyclic group”are 1-pyrrolidinyl, morpholino, piperidino, oxazolidino, and the like.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows changes in the amount of urinary protein excretion withtime course after E30 injection.

FIG. 2 shows the number of PCNA positive cells per single glomerulus innon-treated group and test compound-treated one 5 days after theinitiation of experiment.

FIG. 3 shows the concentration of blood urea nitrogen in non-treatedgroup and test compound-treated one 5 days after the initiation ofexperiment.

FIG. 4 shows the concentration of plasma creatinine in non-treated groupand test compound-treated one 5 days after the initiation of experiment

FIG. 5 shows the ratio of ³H-thymidine incorporation with time coursevarying with the concentration of test compound to investigate theinfluence on the proliferation of cultured mesangial cells.

BEST MODE FOR CARRYING OUT THE INVENTION

The effect as a treating or preventing agent is tested below.

(Animals)

Five to eight weeks old male Slc-Wistar rats were used in theexperiment.

(Procedure for the Establishment of Nephritogenic Antibody)

Mouse monoclonal antibodies are established against rat glomeruli andthe monoclonal antibodies which induced nephritis are screened asdescribed below.

To induce glomerulonephritis by the injection of antibody, the presenceof the antigen on the cell surface is required. First of all, weinvestigated by immunofluorescence whether or not obtained monoclonalantibodies accumulate in the glomeruli after the intravenous injectionto rats. The antigen recognized each clone of monoclonal antibodies wasdefined its distribution and molecular weight. Furthermore,nephritis-inducing activity was evaluated based on the urinary excretionof protein within a week after single injection of antibody.

During this study, a monoclonal antibody E30 was established (J.J.N.,vol. 36, p106, 1994). It has been known that E30 recognizes the surfaceantigen of mesangial cells by the immunohistochemical study, and thatsingle administration of E30 to rats induces complement-dependentmesangial cell injury. The pathological changes are described below.

E30 antibodies immediately bind to the surface antigens of mesangialcells in glomeruli after a intravenous injection to rats, followed bythe activation of compliment system within 30 min. And then,degeneration and necrosis of mesangial cells are occurred, resulting inthe detachment of glomerular basement membrane from mesangial area. Aseries of these pathological features is known as mesangiolysis.Accumulation of platelet and infiltration of inflammatory cells such aspolymorphonuclear leukocyte and macrophage are observed duringmesangiolysis. Mesangiolysis is prominent 1-3 days after the injectionof the antibody and mesangial expansion is frequently observed at thattime. Proliferation of glomerular cells, mainly mesangial cells, isinitiated 3-5 days after the injection, resulting in the morphologicalfeatures of mesangial proliferative glomerulonephritis by a week. Thereconstruction of the glomerular capillary network is accompanied withmitosis and proliferation of mesangial cells and irregular patterns ofangiogenesis. After then, increased number of mesangial cells andoverproduced extracellular matrix are resolved with time course and thepathological features recover to the normal one by a month.

Thus, since a single injection of the monoclonal antibody induces areproducible nephritis model, the antibody-induced nephritis model isuseful for grasping a basic changes in glomerular disease as abiological response.

In Asia, a half of the patients with glomerulonephritis was diagnosed asIgA nephropathy. IgA nephropathy is characterized as IgA deposition toglomerular mesangial cells. IgA nephropathy belongs to proliferativenephritis caused by immunoreaction against mesangial cell itself.Therefore, the monoclonal antibody-induced nephritis model is alsouseful for studying the pathogenesis of IgA nephropathy.

In addition, the monoclonal antibody, E30, is available for establishingsome chronic nephritis models induced by the combination dosing withpuromycin aminonucleoside (J.J.N., vol. 39, p220, 1997) or by a singleinjection of it to uni-nephrectomized rats (J.J.N., vol. 39, p300,1997). The preventing or treating effects of test compounds on thedevelopment of glomerulosclerosis could be evaluated by utilizing thesechronic nephritis models. Similar experiments can be examined by usingfollowing methods: 1) methods by using other monoclonal antibodies oranti-thymocyte serum instead of E30, 2) methods by using hereditarynephrosis rats or mice, 3) methods by using spontaneously diabetic ratsor mice, and 4) methods by using streptozotocin- or alloxan-induceddiabetic rats or mice.

(Protocol for Assay)

In order to induce glomerulonephritis, E30 of 20 to 500 μg, preferably50 to 200 μg, is intravenously injected to rats of five to eight weeksold. Test compounds of 0.1 to 500 mg, preferably 1 to 200 mg, aresuspended with 3 to 10%, preferably 4 to 6%, gum arabic solution and thelike, and are orally given 1 to 5 hours, preferably 1.5 to 3 hours,prior to E30 injection. Constant amount of test compounds are thenconsecutively given 1 to 3 times a day. Evaluation of test compounds aredetermined by the amount of urinary protein excretion 2 days after E30injection when proteinuria reaches to the maximum level.

As for some compounds which exhibit antiproteinuric effects in themethod described above, the amount of urinary protein excretion during 5to 8 days, changes in body weight, morphological changes in glomeruli byautopsy, inhibitory ratio of mesangial proliferation and renal functionare assessed after the treatment of these compounds.

Determination of the amount of urinary protein excretion is performed bythe collection of 24-hour urine samples with stainless metabolic cagesfollowed by the measurement of the concentration of urinary protein.Blood samples obtained at the follow-up period are processed for thedetermination of blood urea nitrogen and plasma creatinine, whichindicate renal function. As a marker of damaged renal tubules, urinaryamounts of N-acetyl-D-glycosaninidase excretion is measured.Furthermore, to study the inhibitory effects of compounds on mesangialproliferation following E30 injection, the number of PCNA (proliferatingcell nuclear antigen) positive cells per single glomerulus is counted.Morphological changes are observed with light and electron microscopy.

The present compound represented by the formula (I) which useful as thecomposition for treating or preventing glomerulopathy is may besynthesized in accordance with the method described in WO97/27174.

The term “compound of the present invention” herein used includespharmaceutically acceptable salt or hydrate of the compound. The salt isexemplified by a salt with alkali metals (e.g., lithium, sodium,potassium, and the like), alkaline earth metals (e.g., magnesium,calcium, and the like), ammonium, organic bases, amino acids, mineralacids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid, and the like), or organic acids (e.g., acetic acid,citric acid, mallein acid, fumaric acid, benzenesulfonic acid,p-toluenesulfonic acid, and the like). These salts can be formed by theusual method.

When the compound of the present invention is administered to a personfor the treatment or prevention of the above diseases, they can beadministered orally as powder, granules, tablets, capsules, pilulae, andliquid medicines, or parenterally as injections, suppositories,percutaneous formulations, insufflation, or the like. An effective doseof the compound is formulated by being mixed with appropriate medicinaladmixtures such as excipient, binder, penetrant, disintegrators,lubricant, and the like if necessary. Parenteral injections are preparedby sterilizing the compound together with an appropriate carrier.

The dosage varies with the conditions of the patients, administrationroute, their age, and body weight. In the case of oral administration,the daily dosage can generally be between 0.1 to 100 mg/kg/day,preferably 1 to 20 mg/kg/day for adult.

The following examples are provided to further illustrate the presentinvention and are not to be constructed as limiting the scope thereof.

Abbreviations described below are used in the following examples.

-   Me: methyl-   tBu: tert-butyl-   DMSO: dimethylsulfoxide-   p-TsOH: p-toluenesulfonic acid    (The Preparation of the Compound)

EXAMPLE 1

Process 1

To a solution of 4.72 g (22.5 mmol) of D-valine tert-butyl esterhydrochloride (XXV)in dichloromethane (100 ml) were added 6.19 ml(2.5×22.5 mmol) of N-methylmorpholine and 6.37 g (1.05×22.5 mmol) of4-phenoxybenzenesulfonyl chloride under ice-cooling. After the mixturewas stirred for 5 h at room temperature, the reaction mixture wasdiluted with ethyl acetate. The organic layer was washed with1N-hydrochloric acid and saturated sodium hydrogencarbonate aq., driedover sodium sulphate, and concentrated in vacuo. The residue wassubjected to silica gel column chromatography and the fraction elutingwith CHCl₃/MeOH=50/1 was collected, recrystallized from ethyl acetateand hexane to yield 8.13 g (Yield 89.1%) of the aimed compound (XXVI),mp. 139-140° C.

IR(KBr, ν max cm⁻¹) 3302, 1731, 1698, 1584, 1489, 1439, 1369, 1342,1299, 1253, 1161, 1136, 1094, 835. NMR (CDCl₃, δ ppm): 0.85(d, J=6.9 Hz,3H), 1.00(d, J=6.9 Hz, 3H), 1.28(s, 9H), 2.05(m, 1H), 3.62(dd, J=4.2,9.6 Hz, 1H), 5.08(d, J=9.6 Hz, 1H),6.97-7.05(m, 2H), 7.18-7.28(m, 4H),7.40(m, 1H), 7.75-7.81(m, 2H). [α]_(D)−44.4±0.8(c=1.008 CHCl₃ 24° C.)

Process 2

To a solution of the compound (XXVI, 3.23 g, 9.41 mmol) indichloromethane (36 ml) was added trifluoroacetic acid (36 ml 50×9.41mmol) and the resulting mixture was stirred for 3 h at room temperature.After stirring for 5 h at room temperature, the solvent was removedunder reduced pressure. The residue was crystallized from ethyl etherand hexane to obtain 2.62 g (yield 96.9%) of the aimed compound (XXVII)(mp. 137-138° C.)

IR(KBr, ν max cm⁻¹) 3154, 1728, 1688, 1583, 1488, 1251 NMR(CDCl₃, δppm): 0.89(d, J=7.0 Hz, 3H), 0.98(d, J=6.8 Hz, 3H), 2.12(m, 1H),3.80(dd, J=4.6, 9.6 Hz, 1H), 5.17(d, J=9.6 Hz, 1H), 6.95-7.08(m, 4H),7.13-7.45(m, 3H), 7.70-7.85(m, 2H) ([α]_(D)−3.7±0.4(c=1.006 DMSO 24° C.)

Process 3

To a solution of the compound (XXVII, 0.3 g, 0.854 mmol) indichloromethane (10 ml) were added oxaryl chloride (0.37 ml, 5×0.854mmol) and a drop of dimethylformamide under ice-cooling and theresulting mixture was stirred for 1 h at room temperature. The reactionmixture was concentrated in vacuo and the residue was dissolved in 10 mlof tetrahydrofuran. A mixed solution of tetrahydrofuran (10 ml) andwater (6 ml) including hydroxylamine hydrochloric acid (474 mg, 8×0.854mmol) and sodium hydrogencarbonate (861 mg, 12×0.854 mmol) was stirredfor 5 min under ice-cooling. To the mixed solution was added the abovementioned acid chloride solution under ice-cooling and the resultingmixture was stirred for 1 h at room temperature. The reaction mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated sodium hydrogencarbonate aq., dried over sodium sulphate, andconcentrated in vacuo. The residue was subjected to silica gel columnchromatography and the fractions eluting with CHCl₃/MeOH=20/1 werecollected, crystallized from hexane to yield 288 mg (Yield 92.5%) of thecompound (1). The results are shown in Table 3.

EXAMPLES 2 TO 6

The compounds (2) to (6) were synthesized in a manner similar to theabove method. The results are shown in Table 3.

TABLE 3 Referential Configuration of example Compound [α]_(D) IR (νcm⁻¹) the asymmetric No. No. (DMSO) mp (° C.) (KBr) carbon 1 1 −11.2 ±0.7 149-151 3628, 1634, 1584, R (25° C., 1488, 1336, 1253, c = 0.705)1157 2 2 110-111 3323, 1678, 1328, R 1150 3 3 82-87 3410, 3276, 1724, R1582, 1488, 1331, 1152 (Nujol) 4 4 115-118 3302, 1667, 1324, R 1153(Nujol) 5 5 241-243 1734, 1719, 1324, R 1160 6 6 224-226 1750, 1324,1159 R 7 7 174-176 1735, 1503, 1343, R 1163

EXAMPLE 7

Process 1

To a solution of the compound (XXVIII, 755 mg, 4.5 ,mmol) in 12 ml ofdichloromethane were added N-methylmorpholine (1.49 ml, 3×4.5 mmol) and5-bromothiophen-2-sulfonylchloride (1.24 g, 1.05×4.5 mmol) underice-cooling. After the reaction mixture was stirred for 15 h at roomtemperature, the resulting mixture was washed with 2N-hydrochloric acid,5% sodium bicarbonate, and water. The organic layer was dried oversodium sulfate and concentrated in vacuo. The residue was subjected tothe silica gel column chromatography and the fractions eluting withethyl acetate/hexane=1/3 were collected, washed with n-hexane to obtainthe aimed compound (XXIX, 1.32 g, yield 82%, mp. 109-110° C.).

[α]_(D)−34.5±0.7(c=1.012 CHCl₃ 25° C.) IR(CHCl₃, ν max cm⁻¹)1737,1356,1164,1138. NMR(CDCl₃, δ ppm): 0.89(d, J=6.8 Hz, 3H), 1.00(d,J=6.8 Hz, 3H), 2.00 (m, 1H), 3.60(s, 3H), 3.83(dd, J=5.2, 10.0 Hz, 1H),5.20(d, J=10.0 Hz, 1H), 7.04(d, J=4.1 Hz, 1H), 7.32(d, J=4.1 Hz, 1H).

Process 2

To a solution of the compound (XXIX, 500 mg, 1.4 mmol) in drytetrahydrofuran (12 ml) were added powder potassium carbonate (387 mg,2×1.4 mmol), 4-methoxyphenylboronic acid (319 mg, 1.5×1.4 mmol), andtetrakis(triphenylphosphine)palladium (81 mg, 0.05×1.4 mmol) and theresulting mixture was stirred for 48 h at 75° C. under argon. Thereaction mixture was diluted with ethyl acetate. The organic layer waswashed with 1N-hydrochloric acid, 5% sodium bicarbonate aq., and water,dried over sodium sulfate, and concentrated in vacuo. The residue wassubjected to silica gel column chromatography and the fractions elutingwith n-hexane/ethyl acetate=3/1 were collected, crystallized fromn-hexane to obtain the aimed compound (XXX, 447 mg, yield 83%, mp.122-123° C.).

Elemental analysis C₁₇H₂₁NO₅S₂ Calcd.: C, 53.25; H 5.52; N, 3.65; S,16.72. Found: C, 53.26; H, 5.50; N, 3.69; S, 16.63.[α]_(D)−21.7±0.6(c=1.000 DMSO 25° C.) IR(KBr, ν max cm⁻¹) 1735, 1605,1505, 1350, 1167, 1136. NMR(CDCl₃, δ ppm): 0.90(d, J=7.0 Hz, 3H),1.00(d, J=6.6 Hz, 3H), 2.10(m, 1H), 3.54(s, 3H), 3.85(s, 3H), 3.87(dd,J=5.0, 10.2 Hz, 1H), 5.20(d, J=10.2 Hz, 1H), 6.94(J=9.0 Hz, 2H), 7.52(d,J=9.0 Hz, 2H), 7.11(d, J=4.0 Hz, 1H), 7.49(d, J=4.0 Hz, 1H)

Process 3

To a solution of the compound XXX, 390 mg, 1.01 mmol) in 8 ml oftetrahydrofuran and 8 ml of methanol was added 5.1 ml of 1 N NaOH, andthe resulting mixture was stirred at 60° C. for 6 h. The reactionmixture was concentrated in vacuo to remove the organic solvents. Theresulting residue was diluted with ethyl acetate. The mixture wasacidified with aqueous solution of citric acid and extracted with ethylacetate. The organic layer was washed with brine, dried over sodiumsulfate, and concentrated in vacuo to give 373 mg (yield 100%) ofcompound (7). The physical data were shown in Table 4.

EXAMPLES 8 TO 30

The compounds (8) to (30) were synthesized in a manner similar to thatdescribed in the above method. The results are shown in Table 4.

TABLE 4 Referential Configuration of example Compound [α]_(D) IR (νcm⁻¹) the asymmetric No. No. (DMSO) mp (° C.) (KBr) carbon 8 8 +23.6 ±0.6 226-230 3415, 1735, 1341, 1159 R (24° C., c = 1.000) 9 9 182-1873260, 1670, 1635, 1430, 1335, 1158 R 10 10 −40.5 ± 1.6 (22° C., 157.5-3431(br), 3280, 1690, 1606, 1352, R c = 0.504, 158.5 1168 MeOH) 11 11−38.5 ± 1.6 (22° C., 140- 3423(br), 3330, 1728, 1686, 1349, R c = 0.502,MeOH) 141.5 1167 12 12 −42.2 ± 1.6 198-202 3422, 3301, 1749, 1362, 1152R (23° C., c = 0.505) 13 13 −65.2 ± 2.1 194-198 3433, 3325, 1748, 1366,1157 R (23° C., c = 0.505) 14 14 +22.6 ± 1.2 3390, 3303, 1746, 1609,1322, 1156 R (27° C., c = 0.504) 15 15 −24.1 ± 1.3 156-158 3433, 3330,1736, 1699, 1346, 1162 R (24° C., c = 0.507) 16 16 −18.2 ± 1.2 182-1843297, 1701, 1606, 1346, 1162 R (27° C., c = 0.506) 17 17 168-170 3277,1719, 1606, 1346, 1159 R 18 18 −1.2 ± 0.9 128-131 3433, 3277, 1715,1606, 1341, 1158 R (26° C., c = 0.504) 19 19 −2.0 ± 0.9 222-224 3310,1752, 1609, 1319, 1159 R (26° C., c = 0.505) 20 20 216-219 3269, 1710,1608, 1323, 1150 R 21 21 180-186 3345, 3306, 1710, 1607, 1354, 1154 R 2222 −2.0 ± 0.9 219-221 3310, 1752, 1609, 1319, 1159 R (26° C., c = 0.505)23 23 270-272 3280, 1723, 1607, 1436, 1335, 1157 R 24 24 +3.0 ± 0.9148-151 3493, 3240, 1714, 1329, 1162 R (27° C., c = 0.501) 25 25 −18.4 ±1.2 220-223 3288, 1716, 1607, 1432, 1320, 1157 R (27° C., c = 0.501) 2626 −13.4 ± 1.1 207-212 3431, 3279, 1709, 1607, 1343, 1163 R (27° C., c =0.507) 27 27 −22.2 ± 1.2 199-200 3463, 3270, 1736, 1608, 1319, 1156 R(27° C., c = 0.500) 28 28 210-212 3333, 3276, 1747, 1610, 1316, 1151 R29 29 214-217 3426, 3357, 1714, 1608, 1330, 1152 R 30 30 +15.6 ±1.1 >230 3417, 3296, 1744, 1322, 1155 R (26° C., c =0.508) decomp.

EXAMPLE 4

Process 1

To a solution of the compound (XXV, 20.94 g, 99.8 mmol) in 200 ml ofdichloromethane were added N-methylmorpholine (22 ml, 2×99.8 mmol)) andp-styrenesulufonyl chloride (20.27 g, 99.8 mmol) under ice-cooling. Theresulting mixture was stirred for 15 h at room temperature. The mixturewas washed with 2N-hydrochloric acid, 5% sodium bicarbonate aq., andwater. The organic layer was dried over sodium sulfate and concentratedin vacuo. The residue was subjected to silica gel column chromatographyand the fractions eluting with ethyl acetate/n-hexane/chloroform=1/3/1were collected, washed with n-hexane to obtain the aimed compound (XXXI,28.93 g yield 85%, mp. 118-120° C.).

IR(KBr, ν max cm⁻¹) 3419, 3283, 1716, 1348, 1168. NMR(CDCl₃, δ ppm):0.85(d, J=6.9 Hz, 3H), 1.00(d, J=6.6 Hz, 3H), 1.21(s, 9H), 2.04(m, 1H),3.62(dd, J=9.8, 4.5 Hz, 1H), 5.09(d, J=9.8 Hz, 1H), 5.41(dd, J=0.5, 10.9Hz, 1H), 5.84(dd, J=0.5, 17.6 Hz, 1H), 6.72(dd, J=10.9, 17.6 Hz, 1H),7.49(d, J=8.4 Hz, 2H), 7.79(d, J=8.4 Hz, 2H).

Process 2

A solution of the compound (XXXI, 5.09 g, 15 mmol) in dichloromethane(300 ml) was treated with ozone at −78° C. for 15 min. To the reactionmixture was added methylsulfide (22 ml, 20×15 mmol) and the resultingmixture was allowed to warm to room temperature gradually over 80 minand concentrated in vacuo to give 6.03 g of aldehyde derivative (XXXII).

IR(CHCl₃, ν max cm⁻¹) 3322, 1710, 1351, 1170. NMR(CDCl₃, δ ppm): 0.85(d,J=6.9 Hz, 3H), 1.00(d, J=6.9 Hz, 3H), 1.22(s, 9H), 2.07(m, 1H), 3.69(dd,J=4.5, 9.9 Hz, 1H), 8.01(s, 4H), 10.08(s, 1H).

Process 3

To a solution of the compound (XXXII, 6.02 g, 15 mmol) in 60 ml ofethanol and 15 ml of tetrahydrofuran was added 2.72 g (1.05×15 mmol) ofbenzenesulfonyl hydrazide at room temperature and the resulting mixturewas stirred for 2 h. The reaction mixture was concentrated in vacuo. Theresidue was column chromatographed on silica gel and the fractionseluting with chloroform/ethyl acetate=1/4 were collected andrecrystallized from ethyl acetate to give the aimed compound (XXXII,4.44 g, mp. 163-164° C., 60% yield from process 2).

Elemental analysis C₂₂H₂₉N₃O₆S₂ Calcd. : C, 53.32; H, 5.90; N, 8.48; S,12.94. Found : C, 53.15; H, 5.87; N, 8.32; S, 12.82.[α]_(D)−11.6±1.0(c=0.509 DMSO 23.5° C.) IR(KBr, ν max cm⁻¹) 3430, 3274,1711, 1364, 1343, 1172. NMR(CDCl₃, δ ppm): 0.84(d, J=6.9 Hz, 3H),0.99(d, J=6.6 Hz, 3H), 1.19(s, 9H), 2.00(m, 1H), 3.63(dd, J=4.5, 9.9 Hz,1H), 5.16(d, J=9.9 Hz, 1H), 7.50-7.68(m, 5H), 7.73(s, 1H), 7.78-7.84(m,2H), 7.96 8.02(m, 2H), 8.16(brs, 1H).

Process 4

To a solution of 4-(methylmercapto)aniline (0.14 ml 1.11×1 mmol) inaqueous 50% ethanol was added 0.3 ml of conc. hydrochloric acid and theresulting mixture was stirred at 0 to 5° C. of the internal temperature.To the mixture was added a solution of sodium nitrite (78.4 mg, 1.14×1mmol) in 1 ml of water and the resulting mixture was stirred for 15 minat the same temperature. To a solution of the compound (XXXIII, 496 mg,1 mmol) in 5 ml of dry pyridine was added the above reaction mixtureover 8 min at −25° C. This mixture was stirred for additional 4 h at−15° C. to room temperature, poured into water, and extracted with ethylacetate. The organic layer was washed with 2N hydrochloric acid, 5%sodium bicarbonate aq., and water, dried over sodium sulfate, andconcentrated in vacuo. The residue was column chromatographed on silicagel and the fractions eluting with chloroform/ethyl acetate=1/9 werecollected to give the aimed compound (XXXIV, 374 mg, yield 74%).

Elemental analysis C₂₃H₂₉N₅O₄S₂.0.3H₂O Calcd.: C, 54.27; H, 5.86; N,13.76; S, 12.60. Found: C, 54.25; H, 5.77; N, 13.87; S, 12.52. IR(KBr, νmax cm⁻¹) 3422, 3310, 1705, 1345, 1171. NMR(d₆-DMSO, δ ppm): 0.83(d,J=6.9 Hz, 3H), 0.86(d, J=7.2 Hz, 3H), 1.19(s, 9H), 2.00(m, 1H), 2.59(s,3H), 3.54(dd, J=6.3, 9.6 Hz, 1H), 7.56(d, J=8.7 Hz, 2H), 8.00(d, J=8.6Hz, 2H), 8.10(d, J=8.7 Hz, 2H), 8.33(d, J=9.6 Hz, 2H), 8.34(d, J=8.7 Hz,2H).

Process 5

A solution of the compound (XXXIV, 353 mg) in 2.5 ml of dichloromethaneand 2.5 ml of trifluoroacetic acid was stirred for 3 h at roomtemperature. The reaction mixture was concentrated in vacuo and theresulting residue was washed with ethyl ether to give the compound (31,308 mg, yield 98%). The results are shown in Table 5.

EXAMPLES 32 TO 62

The compounds (32) to (62) were synthesized in a manner similar to thatdescribed in the above method. The results are shown in Tables 5 and 6.

TABLE 5 Referential Configuration of example Compound [α]_(D) IR (νcm⁻¹) the asymmetric No. No. (DMSO) mp (° C.) (KBr) carbon 31 31 194-1951720, 1343, 1166 R 32 32 215-216 3700-2200, 3278, 1634, 1337, R 1160 3333 −2.8 ± 0.9 194-195 3700-2200, 3278, 1634, 1337, R (21.5° C., c =0.499) 1160 34 34 188-190 2500-3600, 3445, 3325, 2104, R 1727, 1687,1347, 1168 35 35 +17.9 ± 1.1 195-196 3700-2200(br), 3411, 3271, R (22°C., c = 0.508) 1749, 1719, 1331, 1165 36 36 +16.0 ± 0.6 203-205 3394,1757, 1738, 1331, 1163 R (22° C., c = 1.004) 37 37 +18.7 ± 0.6 199-2013468, 1718, 1685, 1334, 1170 R (25° C., c = 1.005) 38 38 −9.9 ± 1.0227-228 3422, 3289, 1696, 1348, 1171 R (24° C., c = 0.503) 39 39 −10.7 ±1.0 208-209 3700-2200(br), 3260, 1746 R (24.5° C., c = 0.504) 1726,1715, 1334, 1170 40 40 −22.9 ± 1.2 205-207 3413, 1700, 1314, 1157 R (23°C., c = 0.510) 41 41 −1.7 ± 0.4 205-207 3286, 1730, 1343, 1165 R (24°C., c = 1.001) 42 42 197-200 3255, 1650, 1510, 1333, 1165 R 43 43 −3.9 ±0.4 208-210 3452, 3351, 1715, 1347, 1167 R (24° C., c = 1.000) 44 44189-191 3441, 3296, 1726, 1686, 1346 R 1168 45 45 −33.4 ± 1.5 (22° C.,188.5- 3432m3292, 1714, 1688, 1347 R c = 0.5009 MeOH) 189.5 1165 46 46−31.3 ± 1.4 (22° C., 175-177 3372, 3334, 3281, 1730, 1712 R c = 0.508MeOH) 1348, 1173 47 47 −9.5 ± 0.5 220-222 3446, 3350, 1711, 1347, 1170 R(24° C., c = 1.003) 48 48 −16.1 ± 1.1 217-219 3358, 3249, 1726, 1336,1163 R (24° C., c = 1.000) 49 49 +1.8 ± 0.8 217-220 3333, 1697, 1732,1344, 1170 S (24° C., c = 0.504) 50 50 217-219 3437, 3332, 1732, 1695,1345 S 1169 51 51 −9.3 ± 1.0 204-206 3289, 1696, 1348, 1175 R 25° C., c= 0.504

TABLE 6 Referential Configuration of example Compound [α]_(D) IR (νcm⁻¹) the asymmetric No. No. (DMSO) mp (° C.) (KBr) carbon 52 52 −32.9 ±1.5 152-154 3298, 1739, 1337, 1163 R (25° C., c = 0.504) 53 53 −11.3 ±1.0 3289, 2231, 1749, 1345, 1167 R (26° C., c = 0.503) 54 54 −9.5 ± 1.0192-193 3329, 1728, 1370, 1172 R (25° C., c = 0.508) 55 55 −11.5 ± 1.03437, 1686, 1609, 1340, 1169 R (25° C., c = 0.500) 56 56 −8.8 ± 1.03262, 1716, 1653, 1337, 1170 R (25° C., c = 0.500) 57 57 +2.4 ± 0.9198-200 3268, 1709, 1346, 1165 R (25° C., c = 0.501) 58 58 −12.7 ± 1.13342, 1719, 1683, 1315, 1161 R (26° C., c = 0.503) 59 59 163-165 3214,1756, 1724, 1345, 1164 R 60 60 −105.4 ± 2.9 216-219 3334, 3165, 1740,1341, 1162 R (27° C., c = 0.501) 61 61 −3.8 ± 0.9 184-187 3190, 1744,1512, 1313, 1143 R (27° C., c = 0.506) 62 62 −5.0 ± 0.9 204-207 3285,1717, 1652, 1604, 1425 R (27° C., c = 0.503) 1342, 1169

EXAMPLE 63

Process 1

To a solution of the compound (XXV, 755 mg, 4.5 mmol) in 12 ml ofdichloromethane were added N-methylmorpholine (1.49 ml, 3×4.5 mmol) and5-bromothiophen-2-sulfonyl chloride (1.24 g, 1.05×4.5 mmol) underice-cooling. After stirring for 15 h at room temperature, the mixturewas washed with 2N-hydrochloric acid, 5% sodium bicarbonate aq., andwater. The organic layer was dried over sodium sulfate and concentratedin vacuo. The resulting residue was subjected to silica gel columnchromatography and the fractions eluting with ethyl acetate/n-hexane=1/3were collected, washed with n-hexane to obtain the aimed compound (XXXV,1.32 g yield 82%, mp. 109-110° C.).

[α]_(D)−34.5±0.7(c=1.012 CHCl₃ 25° C.) IR(CHCl₃, ν max cm⁻¹) 1737, 1356,1164, 1138. NMR(CDCl₃, δ ppm): 0.89(d, J=6.8 Hz, 3H), 1.00(d, J=6.8 Hz,3H), 2.00 (m, 1H), 3.60(s, 3H), 3.83(dd, J=5.2, 10.0 Hz, 1H), 5.20(d,J=10.0 Hz, 1H), 7.04(d, J=4.1 Hz), 7.32(d, J=4.1 Hz, 1H).

Process 2

To a degassed solution of the compound (XXXV, 400 mg, 1.12 mmol) in 5 mlof dimethylformamide were added 4-methoxyphenylacetylene (222 mg,1.5×1.12 mmol) and copper iodide (I) (21 mg, 0.1×1.12 mmol) under anargon atmosphere. Bis(triphenylphosphine)palladium dichloride (II) (39mg, 0.05×1.12 mmol) and triethylamine (0.47 ml, 3×1.12 mmol) were addedto the reaction mixture. The resulting mixture was degassed and stirredovernight under an argon atmosphere at 50° C. The reaction mixture wasdiluted with ethyl acetate. The organic later was washed with1N-hydrochloric acid, 5% sodium bicarbonate, and water, dried oversodium sulfate, and concentrated in vacuo. The resulting residue wascolumn chromatographed on silica gel. The fractions eluting withn-hexane/ethyl acetate=2/1 were collected and recrystallized from ethylacetate/n-hexane to give the aimed compound (XXXVI, 392 mg, yield 86%,mp. 131-132° C.).

Elemental analysis C₁₉H₂₁NO₅S₂.0.2 H₂O Calcd.: C, 55.51; H, 5.25; N,3.41; S, 15.60. Found: C, 55.80; H, 5.19; N, 3.38; S, 15.36. IR(KBr, νmax cm⁻¹) 3268, 2203, 1736, 1604, 1524, 1348, 1164. NMR(CDCl₃, δ ppm):0.90(d, J=6.6 Hz, 3H), 1.00(d, J=7.0 Hz, 3H), 2.00(m, 1H), 3.60(s, 3H),3.84(s, 3H), 3.86(dd, J=5.0, 10.2 Hz, 1H), 5.21(d, J=10.2 Hz,1H),6.90(d, J=9.0 Hz, 2H), 7.44(d, J=9.0 Hz, 2H), 7.12(d, J=4.0 Hz, 1H),7.44(d, J=4.0 Hz, 1H).

Process 3

To a solution of the compound (XXXVI, 407 mg, 1 mmol) in 8 ml oftetrahydrofuran and 8 ml of methanol was added 5.1 ml of 1N NaOH. Theresulting mixture was stirred for 6 h at 60° C. The reaction mixture wasconcentrated in vacuo to remove an organic solvent, and the residue wasdiluted with ethyl acetate. The mixture was acidified with aqueoussolution of citric acid and extracted with ethyl acetate. The organiclayer was washed with brine, dried over sodium sulfate, and concentratedin vacuo to give compound (63, 373 mg, yield 100%). The results areshown in Table 7.

EXAMPLES 64 TO 89

The compounds (64) to (89) were synthesized in a manner similar to thatdescribed in the above method. The results are shown in Tables 7 and 8.

TABLE 7 Referential Configuration of example Compound [α]_(D) IR (νcm⁻¹) the asymmetric No. No. (DMSO) mp (° C.) (KBr) carbon 63 63 194-1951710, 1604, 1351, 1216 R 64 64 −7.6 ± 1.0 157-158 3268, 2208, 1712,1430, 1414, R (25° C., c = 0.503) 1350, 1163, 1143 65 65 191-193 3290,3200, 1670, 1650 (Nujol) R 66 66 −3.5 ± 0.4 153-154 3280, 3234, 1723,1486, 1423, R (22° C., c = 1.004) 1345, 1228, 1150, 1115, 1088, 1014,830, 811, 699 67 67 149-150 1695, 1334, 1184 R 68 68 180-182 1729, 1675,1340, 1168 R 69 69 1605, 1523, 1340, 1151 R 70 70 201-202 3389, 3370,2207, 1666, 1427, R 1329, 1161 71 71 182-187 3260, 1670, 1635, 1335,1160 R 72 72 3410, 2919, 2207, 1668, 1593, R 1519, 1487, 1457, 1426 7373 +19.8 ± 0.6 227-229 1736, 1618, 1398, 1168 R (23° C., c = 1.008) 7474 196-199 3408, 3381, 3296, 3264, 2218, 1676, 1642 1605, 1590, 1568, R1556, 1516, 1457, 1425 75 75 −8.4 ± 0.5 148-149 3329, 2209, 1703, 1351,1167 R (22.5° C., c = 1.005) 76 76 +21 ± 0.6 171-173 3431, 2205, 1713,1353, 1161 R (22.5° C., c = 1.012) 77 77 −6.6 ± 0.5 208-209 3335, 2202,1733, 1351, 1163 R (23° C., c = 1.008) 78 78 +20.1 ± 0.6 3383, 2202,1747, 1323, 1158 R (23° C., c = 1.000) 79 79 −15.6 ± 0.6 156-157 3260,2206, 1709, 1351, 1162 R (23° C., c = 1.001) 80 80 3410, 2207, 1668,1593, 1338, R 1156 81 81 +10.3 ± 1.0 218-219 3459, 3384, 2208, 1720,1338, R (26° C., c = 0.504) 1159 82 82 3412, 3257, 2202, 1741, 1604, R1338, 1156 83 83 +19.9 ± 0.6 224-226 3406, 3254, 2203, 1723, 1341, R(24° C., c '2 4.007) 1161

TABLE 8 Referential Configuration of example Compound [α]_(D) IR (νcm⁻¹) the asymmetric No. No. (DMSO) mp (° C.) (KBr) carbon 84 84 −8.9 ±0.5 204-207 3513, 3227, 2205, 1712, R (24° C., c = 1.000) 1330, 1162 8585 −4.6 ± 0.5 215-217 3491, 3263, 2207, 1720, R (24° C., c = 1.002)1354, 1338, 1160 86 86 +18.5 ± 2.9 214-218 3402, 3308, 2199, 1736, R(26° C., c = 0.205) 1380, 1344, 1162 87 87 −12.4 ± 1.0 158-160 3336,3166(br), 2193, 1735, R (27° C., c = 0.502) 1698, 1377, 1164 88 88 +22.7± 1.3 227-229 3600-2400(br), 1736, R (25° C., c = 0.500) 1618, 1398,1168 89 89 196-199 3408, 3296, 2218, 1676, R 1642, 1376, 1355, 1164

EXAMPLE 90

Process 1

To a solution of the compound (XXXVII, 5.0 g, 12.8 mmol) in 50 ml ofdichloromethane were added N-methylmorpholine (4.2 ml, 3×12.8 mmol),p-nitrobenzenesulfonyl chloride (3.78 g, 1.2×12.8 mmol) underice-cooling. The reaction mixture was stirred over night and washed with2N-hydrochloric acid, 5% sodium bicarbonate aq., and water. The organiclayer was dried over sodium sulfate and concentrated in vacuo. Theresulting residue was recrystallized from acetone-n-hexane to obtain theaimed compound (XXXVIII, 5.05 g, yield 97.8%, mp. 172-174° C.)

IR(KBr, ν max cm⁻¹) 3417, 3281, 1745, 1529, 1353, 1168. NMR(d₆-DMSO, δppm): 2.85(dd, J=9.8, 14.6 Hz, 1H), 3.08(dd, J=4.8, 14.4 Hz, 1H),3.56(s, 3H), 4.02(m, 1H),6.84-7.30(m, 5H), 7.53(d, J=8.6 Hz, 2H),7.94(d, J=8.6 Hz, 2H), 8.83(brs, 1H), 10.37(s, 1H).[α]_(D)+43.5±1.6(c=0.508 DMSO 25° C.)

Process 2

A solution of the compound (XXXVIII, 5.0 g) in 50 ml of methanol and 10ml of dimethylformamide was hydrogenated using 10% Pd/C (1 g) for 1 h atroom temperature. The reaction mixture was filtered off and the filtratewas concentrated in vacuo. The residue was recrystallized fromchloroform/ethyl ether to give the aimed compound (XXXIX, 3.43 g, yield74.1%, mp. 158-160° C.)

IR(KBr, ν max cm⁻¹) 3468, 3378, 3283, 1737, 1623, 1596, 1335, 1320,1155. NMR(d₆-DMSO, δ ppm): 2.85(dd, J=6.6, 14.2 Hz, 1H), 3.00(dd, J=8.2,14.2 Hz, 1H), 3.30(s, 3H), 3.86(m, 1H), 5.93(s, 2H), 6.56(d, J=8.8, 2H),6.90-7.10(m, 3H), 7.20-7.38(m, 2H). [α]_(D)+10.1±1.0(c=0.503 DMSO 25°C.)

Process 3

To a solution of the compound (XXXIX, 500 mg, 1.3 mmol) in 13 ml ofdichloromethane were added N-methylmorpholine (0.29 ml, 2×1.3 mmol) andp-bromobenzoyl chloride (371 mg, 1.3×1.3 mmol) under ice-cooling and theresulting mixture was stirred over night at room temperature. Methylethyl ketone was added to the reaction mixture and the mixture waswashed with 2N-hydrochloric acid, 5% sodium bicarbonate aq., and water.The organic layer was dried over sodium sulfate and concentrated invacuo. The residue was recrystallized from acetone-n-hexane to give theaimed compound (XL, 720 mg, yield 100%, mp. 215-218° C.)

IR(KBr, ν max cm⁻¹) 3397, 3330, 1787, 1732, 1668, 1348, 1337, 1157.NMR(d₆-DMSO, δ ppm): 2.90(dd, J=8.0, 13.4 Hz, 1H), 3.33(s, 3H), 3.06(dd,J=7.0, 14.8 Hz, 1H), 3.97(dt, J=8,2, 8,2 Hz, 1H), 6.90-7.10(m, 3H),7.24-7.32(m, 2H), 7.62(d, J=8.8 Hz, 2H), 7.78(d, J=8.4 Hz, 2H), 7.86(d,J=8.4 Hz, 2H), 7.93(d, J=8.8 Hz, 2H), 8.07d, J=8.8 Hz, 1H), 8.39(d,J=8.8 Hz, 1H), 10.59(s, 1H). [α]_(D)−1.9±0.8(c=0.51 DMSO 25° C.)

Process 4

To a solution of the compound (XL, 807 mg) in 6 ml of dimethylsulfoxidewas added 2.9 ml of 1N NaOH. The resulting mixture was stirred for 5 hat room temperature. Water was added to the mixture and acidified with2N-hydrochloric acid. The precipitated crystal are collected and washedwith water to give compound (90, 720 mg, yield 78.7%). The results areshown in Table 9.

EXAMPLES 91 TO 94

The compounds (91) to (94) were synthesized in a manner similar to thatdescribed in the above method. The results are shown in Table 9.

TABLE 9 Referential Configuration of example Compound IR (ν cm⁻¹) theasymmetric No. No. [α]_(D) mp (° C.) (KBr) carbon 90 90 +3.0 ± 0.9215-218 2800-3640, 3328, 1727, R (25° C., c = 0.501) 1668, 1590, 1514,1316, 1154 91 91 211-213 1719, 1629, 1340, 1156 R 92 92 170-175 1730,1651, 1603, 1333, R 1161 93 93 242-244 2840-3600, 3346, 1752, R 1726,1656, 1610, 1324, 1160 94 94 235- 2550-3600, 3318, 1742, R 235.5 1667,1591, 1334, 1161

EXAMPLES 95 TO 100

The compounds (95) to (100) were synthesized in a manner similar to thatdescribed in WO 97/27174 and the above method. The results are shown inTable 10.

TABLE 10 Referential Configuration of example Compound IR (ν cm⁻¹) theasymmetric No. No. [α]_(D) mp (° C.) (KBr) carbon 95 95 −29.4 ± 1.4166-169 3437, 1737, 1376, 1162 R (25° C., c = 0.504) 96 96 −32.0 ± 1.4178-179 3280, 1702, 1351, 1165 R (25° C., c = 0.503) 97 97 −9.2 ± 1.0184-186 3282, 1711, 1354, 1164 R (25° C., c = 0.503) 98 98 220-223 3202,1748, 1707, 1376, R 1156 99 99 −9.9 ± 1.0 227-230 3258, 1725, 1362, 1159R (26° C., c = 0.504) 100 100 −6.2 ± 0.9 203-205 3437, 3318, 1709, 1343,R (24° C., c '2 0.503) 1162

EXAMPLE 101

Process 1

A solution of benzenesufonylhydrazide (1.722 g, 10 mmol) and thecompound (XLI, 1.43 ml, 1.05×10 mmol) in 20 ml of ethanol and 2 ml oftetrahydrofuran was stirred for 3 h at room temperature. Water was addedto the reaction mixture and the mixture was extracted with ethylacetate. The organic layer was washed with 2N-hydrochloric acid, brine,and brine, dried over sodium sulfate, and concentrated in vacuo. Theresidue was crystallized from hexane/ethyl acetate to give the compound(XLII, 2.873 g, yield 87.5%, 142-144° C.).

IR(KBr, ν max cm⁻¹) 3431, 3178, 1325, 1169, 1123. ¹H NMR (CDCl₃, δ ppm):7.51-7.72 (m, 2H), 7.79 (s, 1H), 7.98-8.04 (m, 2H), 8.24 (br s, 1H).Elemental analysis C₁₄H₁₁F₃N₂O ₂S Calcd.: C, 51.22; H, 3.38; F, 17.36;N, 8.53; S, 9.77. Found: C, 51.22; H, 3.38; F, 17.50; N, 8.59; S, 9.69.

Process 2

To a solution of the compound (XLIII, 572 mg, 2 mmol) in 20 ml of 50%ethanol aq. was added 0.84 ml of conc. hydrochloric acid and theresulting mixture was stirred at 0 to 5° C. of the internal temperature.To the mixture was added a solution of sodium nitrite (168 mg, 1.2×2mmol) in 3 ml of water and the resulting mixture was stirred for 20 minat the same temperature. A solution of the compound (XLII, 657 mg, 2mmol) in 20 ml of pyridine was stirred at −25° C. To the pyridinesolution was added to the above reaction mixture and the resultingmixture was stirred for 1 h at the same temperature and stirred overnight at room temperature. Water was added to the reaction mixture andthe resulting mixture was extracted with ethyl acetate. The organiclayer was washed with 2N hydrochloric acid, 1 N potassium hydroxide, andsaturated brine, dried over sodium sulfate, and concentrated in vacuo.The residue was column chromatographed on silica gel and the fractionseluting with chloroform/methanol=50/1 were collected, recrystallizedfrom acetone/hexane to give compound XLIV, 637 mg, yield 65.9%, mp.189-191° C.).

IR(KBr, ν max cm⁻¹) 3282, 1735, 1350, 1328, 1165, 1127. ¹H NMR (CDCl₃, δppm): 0.90 (d, J=6.9 Hz, 3H), 1.00 (d, J=6.6 Hz, 3H), 2.10 (m, 1H), 3.52(s, 3H), 3.85 (dd, J=4.8, 9.9 Hz, 1H), 5.23 (d, J=9.9 Hz, 1H), 7.79-7.85(m, 2H), 8.05-8.10 (m, 2H), 8.36-8.42 (m, 4H). [α]_(D)+3.9±0.9 (c=0.512, DMSO, 25° C.) Elemental analysis C₂₀H₂₀F₃N₅O₄S Calcd.: C, 49.69;H, 4.17; F, 11.79; N, 14.49; S, 6.63. Found: C, 49.52; H, 4.17; F,11.73; N, 14.50; S, 6.66.

Process 3

To a solution of the compound (XLIV, 637 mg, 1.32 mmol) in 8 ml oftetrahydrofuran and 8 ml of methanol was added 1N KOH. The resultingmixture was stirred over night at 60° C. The reaction mixture wasacidified with 2N hydrochloric acid and extracted with ethyl acetate.The organic layer was washed with brine, dried over sodium sulfate, andconcentrated in vacuo. The residue was recrystallized fromacetone/hexane to give compound (101, 585 mg, yield 94.4%, mp. 198-200°C.). The results are shown in Table 11.

EXAMPLES 102 TO 121

The compounds (102) to (121) were synthesized in a manner similar tothat described in the above method. The results are shown in Table 11.

TABLE 11 Referential Configuration of example Compound [α]_(D) IR (νcm⁻¹) the asymmetric No. No. (DMSO) mp (° C.) (KBr) carbon 101 101 −4.2± 0.9 203-208 3430, 3290, 1701, 1610, 1344, R (27° C., c = 0.506) 1164102 102 −9.1 ± 1.0 224-226 3409, 3329, 1741, 1610, 1590, R (26° C., c =0.504) 1321, 1163 103 103 −17.4 ± 1.1 243-245 3335, 1725, 1348, 1168 R(27° C., c = 0.506) 104 104 −7.7 ± 1.0 198-200 3270, 1746, 1326, 1160 R(25° C., c = 0.504) 105 105 190-192 3339, 3287, 1719, 1690, 1350, R 1167(Nujol) 106 106 −9.4 ± 1.0 204-205 3317, 3232, 1762, 1746, 1379, R (25°C., c = 0.500) 1161 (Nujol) 107 107 −11.7 ± 1.0 186-187 3302, 3215,1762, 1746, 1378, R (25° C., c = 0.505) 1161 (Nujol) 108 108 −2.2 ± 0.8187-189 3184, 1739, 1322, 1146(Nujol) R (25° C., c = 0.505) 109 109+31.9 ± 1.4 125-126 3384, 3268, 1761, 1712, 1332, R (25° C., c = 0.502)1159 (Nujol) 110 110 188-190 3182, 1739, 1322, 1146 S (Nujol) 111 111+33.7 ± 1.5 113-115 3286, 1732, 1683, 1328, 1162 R (25° C., c = 0.504)(Nujol) 112 112 +7.8 ± 1.0 179-181 3293, 1713, 1348, 1145 S (25° C., c =0.502) (Nujol) 113 113 −6.8 ± 0.9 153-154 3179, 1741, 1709, 1324, 1146 R(25° C., c = 0.504) (Nujol) 114 114 194-195 3269, 1709, 1351, 1152 R(Nujol) 115 115 191-192 3445, 3288, 1719, 1670, 1595, R 1450, 1350, 1163116 116 199-201 3316, 2962, 1715, 1341, 1156 R 117 117 155-157 3272,1709, 1350, 1152 R 118 118 −7.9 ± 1.0 187-189 3316, 1744, 1309, 1161 R(26° C., c = 0.504) 119 119 −8.0 ± 1.0 185-188 3284, 1726, 1370, 1167, R(26° C., c = 0.503) 120 120 −9.1 ± 1.0 194-196 3313, 1739, 1343, 1164 R(26° C., c = 0.504) 121 121 −9.6 ± 1.0 191-193 3263, 1740, 1329, 1159 R(26° C., c = 0.502)

TEST EXAMPLE Test Example 1

5-week-old male Slc-Wistar rats were reared under the conditions of roomtemperature of 25° C., 40-60% humidity and 12 hour cycles of light anddarkness and fed on solid chow (CA-1, Clea Japan) and tap water adlibitum. After one week's preliminary rearing, each rat was housed in astainless metabolic cage for acclimation for one week, and was used forexperiment at 7 weeks of old (body weight: 150-180 g). E30 monoclonalantibody (J.J.N., vol. 36, p106, 1994) was diluted with saline at 100μg/0.4 ml and was administered from tail vein at the volume of 0.4ml/body. Compound (2) was suspended with 5% gum arabic solution and wasgiven at the dose of 100 mg 2 hours before E30 injection. Subsequently,compound (2) of 100 mg was orally administered once a day from the nextday. The rats were housed in stainless metabolic cages just after theadministration of test compound, and then 24-hour urine samples werecollected. After measuring the volume, the urine was centrifuged at 3000rpm for 10 min at room temperature. The supernatant was used for thedetermination of urinary excretion of protein. Urinary protein wasdetermined by pyrogallole red method (Micro TP-test Wako, WakoZyunyaku). The amount of urinary protein excretion on day 2 incompound-treated group was compared with that in vehicle-treated one,and inhibitory ratio of urinary protein excretion was calculated. Theresults are shown in Table 11. The compounds (1) and (3) to (121) wereexamined in a manner similar to that described in the above method andthe results are shown in Table 12. FIG. 1 shows the change in urinaryexcretion of protein throughout the experiment.

TABLE 12 Compound Inhibitory No. rate (%) 1 44.6 2 31.1 3 28.9 4 56.3 521.6 6 27.1 7 48.0 8 14.4 9 30.5 10 2 11 12.2 12 33.4 13 17.8 16 32 2411.5 26 10.7 31 40.9 32 56.5 33 25.5 35 50.7 36 22.1 37 33.6 38 29.4 3949.7 40 10.2 41 16 44 19 63 36.0 64 36.7 65 37.6 66 31.3 67 13.5 69 25.570 25.8 71 30.4 72 21.1 73 14 80 21.1 81 9 82 22.8 84 26.6 86 34 88 25.689 36.5 90 31.2 91 52.0 92 54.3 93 29.3 94 21.5 95 21 101 29 104 27 10835 114 2.7

On the follow-up day (day 5), animals were subjected to ventrotomy underanesthesia with pentobarbital, and then, kidneys were removed immediateafter blood collection, fixed in 10% formalin or methacarn solution. Thetissue samples fixed with formalin were embedded in paraffin. Sectionswere stained with the periodic acid-Schiff reaction and processed forlight microscopy. On the other hand, the paraffin sections of tissuesamples fixed with methacarn solution were processed forimmunohistochemistry with anti-PCNA antibody (mouse anti-PCNA IgG).After then, the number of PCNA positive glomerular cells belonging to Sphase within the cell cycle were counted. The result is shown in FIG. 2.

On the follow-up day (day 5), blood samples were collected and processedfor the determination of blood urea nitrogen and plasma creatinine.Concentration of blood urea nitrogen was measured with Creatinine-testWako (Wako Zyunyaku). The result is shown in FIG. 3. Concentration ofplasma creatinine was determined with Urea nitrogen B-test Wako (WakoZyunyaku). The result is shown in FIG. 4.

Test Example 2

Mesangial cells isolated from glomeruli of male Wistar rats aged 4 weeksold were plated on wells of a 96-well tissue culture plate at a densityof 1000 cells per well and cultibated in RPMI medium containing 20%fetal calf serum for 24 hours. Following incubation for 20 or 44 hours,³H-thymidine (100000 dpm/well) was added in the cell-culture medium.Four hours later, cultured mesangial cells were washed followed by celllysis with 0.1% SDS and deoxycholate (0.1 mg/ml). Measurement ofincorporation of ³H-thymidine was determined by counting radio activitywith liquid scintillation counter, and the ratio of incorporation wascalculated. The result is shown in FIG. 5.

From the results summarized in FIG. 1 and Table 12, it has been provedthat the amount of urinary protein excretion in test compound-treatedgroup decrease significantly. It is known that the increase of urinaryprotein excretion is well associated with damaged glomeruli (as same asin human), therefore, proteinuria is a good indicator of renaldysfunction. After the injection of E30, the amount of the urinaryprotein excretion remarkably increased. Renal function in rats with E30monoclonal antibody became detrimental. In test compound-treated group,urinary protein excretion was significantly suppressed, indicating thatthe compound served as a preventing or treating agent against glomerularinjury.

As shown in FIG. 2, cell proliferation was suppressed in testcompound-treated group. Extraordinary proliferation of mesangial cellsare observed in glomeruli 5 days after a injection of monoclonalantibody (observation with light and electron microscopy). Theproliferating cells could be detected by immunohistochemistry with PCNAantigen expressing during S phase within the cell cycle. Therefore,comparison study of the number of PCNA positive cells per singleglomerulus between vehicle-treated group and test compound-treated oneprovided the evidence as described above.

FIG. 3 shows that concentration of blood urea nitrogen in testcompound-treated group decreased significantly. Therefore, decrease inrenal function (glomerular filtration rate) was modified by thetreatment of test compound, indicating that the compound served as apreventing or treating agent against glomerular injury.

FIG. 4 shows that concentration of plasma creatinine in testcompound-treated group decreased significantly. Therefore, decrease inrenal function (glomerular filtration rate) was modified by thetreatment of test compound, indicating that the compound served as apreventing or treating agent against glomerular injury.

FIG. 5 shows that the test compound inhibited serum-induced mesangialproliferation in a dose-dependent manner. This experiment was designedto define whether the inhibitory effect of the test compound onmesangial proliferation, as shown in FIG. 2, was originated from itsdirect effect (on the cells) or not

As shown in the above results, it is clearly recognized that thecompounds of the present invention suppress the amount of urinaryprotein excretion and the proliferation of mesangial cells mostlyobserved in glomerulopathy. The state of a disease occurred in theseexperimental models is similar to the human glomerulonephritis anddiabetic nephropathy. Therefore, the compounds of the present inventionare useful for a composition for preventing or treatingglomerulonephritis and diabetic nephropathy.

Test Example 3 Assay for Inhibitory Activities of MMP-9 and MMP-2

The enzymatic activity was analyzed on the method described by Knight,C. G., et al. (C. Graham Knight., Frances Willenbrock and Giman Murphy:A novel coumarin-labelled peptide for sensitive continuous assays of thematrix metalloproteinases. FEBS Lett., 296 (1992) 263-266).

MMP-9 was purified by using a combination of procedures described inprevious reports as follows. Yasunori Okada, Yukio Gonoji, Katsumi Naka,Katsuro Tomita, Isao Nakanishi, Kazushi Iwata and Taro Hayakawa: Matrixmetalloproteinase 9 (92-kDa gelatinase/type IV collagenase) from HT1080human fibrosarcoma cells. Purification and activation of the precursorand enzymic properties. J. Biol. Chem., 267 (1992) 21712-21719. YasunoriOkada, Tatsuhisa Morodomi, Jan J, Enghild, Ko Suzuki, Atsushi Yasui,Isao Nakanishi, Guy Salvesen and Hideaki Nagase: Matrixmetalloproteinase 2 from human rheumatoid synovial fibroblasts.Purification and activation of the precursor and enzymic properties.Eur. J. Biochem. 194 (1990) 721-730. Robin V Ward, Rosalind M Hembry,John J Reynolds and Gillian Murphy: The purification of tissue inhibitorof metalloproteinase-2 from its 72 kDa progelatinase complex. Biochem.J. 278 (1991) 179-187.

Briefly, human fibrosarcoma ATCC HT1080 cell line was cultured toconfluent in Dulbecco's Modified Medium (DMEM) containing 10% fetal-calfserum at 37° C. for 48 hours. Subsequently, the medium of confluentculture was changed to serum-free DMEM medium. To obtain MMP-9,Phorbol-12-myristate-13-acetate (TPA) must be added to this serum-freeDMEM medium at a concentration of 50 ng/ml. The TPA treated medium wascentrifuged at 3000 rpm for 15 min and the supernatant was concentratedto 450 ml by a Toyo-Roshi UP-20 apparatus with an ultrafiltrationmembrane. Then, proMMP-9 in this concentrated solution was purified byusing columns of Gelatin-Sepharose and Concanavalin A-Sepharose. Thepool containing proMMP-9 was dialyzed, concentrated (Toyo-Roshi UP-20)and applied to columns of Sephacryl S-200 and Green A matrix for theseparation from TIMPs. The obtained proMMP-9 fraction was activated byTPCK-Trypsin (final conc. 3 μg/μl reaction mix.) for the assay.

MMP-2 was purchased from Yagai (Yamagata pref., Japan).

MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH₂ as a substrate was purchasedfrom Petide Institute(Osaka pref., Japan). This substrate was dissolvedin DMSO at a concentration of 1 mM.

Reaction buffer consists of 50 mM Tris-HCl buffer (pH 7.5) containing 10mM CaCl₂, 0.3 M NaCl, 0.005% Brij35 and 0.01% NaN₃.

Assay method of inhibitory activity against MMP-9:

1.0 μl of a tested compound in DMSO is added to 48.0 μl of a reactionbuffer containing 0.08 μl of an enzyme solution. After standing for 60minutes at room temperature, the reaction was started by adding 1.0 μlof a substrate solution. After incubation for 60 minutes at roomtemperature, 100 μl of 3% (v/v) AcOH for reaction stopping and measureda fluorescence with excitation and emission at 320 nm and 405 nm,respectively (Spectrophotofluorometer; Fluoroscan Ascent (Labsystem)).

Assay Method of Inhibitory Activity Against MMP-2:

1.0 μl of a tested compound in DMSO is added to 48.0 μl of a reactionbuffer containing 0.05 μl of an enzyme solution. After standing for 60minutes at room temperature, the reaction was started by adding 1.0 μlof a substrate solution. After incubation for 60 minutes at roomtemperature, 100 μl of 3% (v/v) AcOH for reaction stopping and measureda fluorescence with excitation and emission at 320 nm and 405 nm,respectively (Spectrophotofluorometer; Fluoroscan Ascent (Labsystem)).

The measurement of the inhibitory activities (IC₅₀) was carried out in afollowing four methods;

A) Reaction with substrate, enzyme and inhibitor

B) Reaction with substrate and inhibitor, without enzyme

C) Reaction with substrate and enzyme, without inhibitor

D) Reaction with substrate only

ICr₅₀ values were calculated by using a following formula and eachfluorescence values of above four methods (A to D).% inhibition={1−(A-B)/(C-D)}×100

IC₅₀ means the concentration required to inhibit 50% of the enzymeactivity. The results are shown in Table 13.

TABLE 13 Compound IC₅₀ (MMP-2) IC₅₀ (MMP-9) No. (μM) (μM) 87 0.0036870.01 95 0.0107 0.019 96 0.0015 0.0362 97 0.01557 0.1360 98 0.0953 0.78799 0.00459 0.04926 103 0.00612 0.0278 104 0.00202 0.01867 105 0.041370.3042 106 0.02827 0.1037 107 0.00351 0.00825 108 0.00992 0.0312 1090.00471 0.0132 110 0.0257 0.0947 111 0.01069 0.1042 112 0.02842 0.1263113 0.005701 0.07179 114 0.02778 0.3161 115 0.181 4.61 116 0.012240.09401 117 0.002619 0.03098 118 0.002159 0.06161 119 0.001693 0.04549120 0.0009195 0.005815 121 0.000561 0.148

FORMULATION EXAMPLE Formulation Example 1

Granules are prepared using the following ingredients.

Ingredients The compound represented by the formula (I) 10 mg Lactose700 mg Corn starch 274 mg HPC-L 16 mg 1000 mg

The compound represented by the formula (I) and lactose were made passthrough a 60 mesh sieve. Corn starch was made pass through a 120 meshsieve. They were mixed by a twin shell blender. An aqueous solution ofHPC-L (low mucosity hydroxypropylcellulose) was added to the mixture andthe resulting mixture was kneaded, granulated (by the extrusion withpore size 0.5 to 1 mm mesh), and dried. The dried granules thus obtainedwere sieved by a swing sieve (12/60 mesh) to yield the granules.

Formulation 2

Powders for filling capsules are prepared using the followingingredients.

Ingredients The compound represented by the formula (I) 10 mg Lactose 79mg Corn starch 10 mg Magnesium stearate 1 mg 100 mg

The compound represented by the formula (I) and lactose were made passthrough a 60 mesh sieve. Corn starch was made pass through a 120 meshsieve. These ingredients and magnesium stearate were mixed by a twinshell blender. 100 mg of the 10-fold trituration was filled into a No. 5hard gelatin capsule.

Formulation 3

Granules for filling capsules are prepared using the followingingredients.

Ingredients The compound represented by the formula (I) 15 mg Lactose 90mg Corn starch 42 mg HPC-L 3 mg 150 mg

The compound represented by the formula (I) and lactose were made passthrough a 60 mesh sieve. Corn starch was made pass through a 120 meshsieve. After mixing them, an aqueous solution of HPC-L was added to themixture and the resulting mixture was kneaded, granulated, and dried.After the dried granules were lubricated, 150 mg of that were filledinto a No. 4 hard gelatin capsule.

Formulation 4

Tablets are prepared using the following ingredients.

Ingredients The compound represented by the formula (I) 10 mg Lactose 90mg Microcrystal cellulose 30 mg CMC-Na 15 mg Magnesium stearate 5 mg 150mg

The compound represented by the formula (I), lactose, microcrystalcellulose, and CMC-Na (carboxymethylcellulose sodium salt) were madepass through a 60 mesh sieve and then mixed. The resulting mixture wasmixed with magnesium stearate to obtain the mixed powder for the tabletformulation. The mixed powder was compressed to yield tablets of 150 mg.

INDUSTRIAL APPLICABILITY

The sulfonamide derivatives of the present invention inhibit theinitiation and progression of the glomerulopathy, especiallyglomerulonephritis and diabetic nephropathy and are useful as thetreating or preventing agent.

1. A method for treating glomerulopathy which comprises administering aneffective amount of a compound of the formula (I) and a pharmaceuticallyacceptable carrier:

wherein R¹ is optionally substituted lower alkyl or optionallysubstituted heteroarylalkyl; R² is hydrogen, optionally substitutedlower alkyl, optionally substituted aryl, or optionally substitutedaralkyl; R³ is 1,4-phenylene; R⁴ is a substituent represented by theformula:

wherein R⁵ is hydrogen atom, hydroxy, optionally substituted loweralkyloxy, mercapto, lower alkylthio, cycloalkyl, halogen, carboxy, loweralkyloxycarbonyl, nitro, cyano, lower holoalkyl, aryloxy, optionallysubstituted amino, guanidino, optionally substituted lower alkyl, loweralkenyl, lower alkynyl, acyl, acyloxy, —CONR^(A)R^(B), —N(R^(C))COR^(D)(wherein R^(A), R^(B), and R^(C) are the same or different selected fromhydrogen atom, lower alkyl, and aralkyl; R^(D) is lower alkyl, aryl, oraralkyl), optionally substituted non-aromatic heterocyclic group, oroptionally substituted heteroaryl; and Y is OH, its optically activesubstance, their pharmaceutically acceptable salt, or hydrate thereof.2. A method for treating glomerulopathy which comprises administering aneffective amount of a compound of the formula (II) and apharmaceutically acceptable carrier:

wherein R¹, R², and R³ are as defined in claim 1; R⁷ is a substituentrepresented by the formula:

wherein R⁸ is hydrogen atom, hydroxy, lower alkyloxy, mercapto, loweralkylthio, cycloalkyl, halogen, carboxy, lower alkyloxycarbonyl, nitro,cyano, lower haloalkyl, aryloxy, optionally substituted amino,guanidino, optionally substituted lower alkyl, lower alkenyl, loweralkynyl, alkanoyl, acyloxy, or optionally substituted heteroaryl; and Yis OH, its optically active substance, their pharmaceutically acceptablesalt, or hydrate thereof.
 3. A method for treating glomerulopathy whichcomprises administering an effective amount of a compound of the formula(I) and a pharmaceutically acceptable carrier:

wherein R¹, R², and R³ are as defined in claim 1: R⁴ is a substituentrepresented by the formula:

wherein R¹⁰ is hydrogen atom, optionally substituted lower alkyloxy,lower alkylthio, halogen, optionally substituted amino, optionallysubstituted lower alkyl, or optionally substituted non-aromaticheterocyclic group; and Y is OH, its optically active substance, theirpharmaceutically acceptable salt, or hydrate thereof.
 4. A method fortreating glomerulopathy which comprises administering an effectiveamount of a compound of the formula (II) and a pharmaceuticallyacceptable carrier:

wherein R¹, R², and R³ are as defined in claim 1; R⁷ is a substituentrepresented by the formula:

wherein R² is hydrogen atom, halogen, nitro, optionally substitutedlower alkyl, lower alkyloxy, or lower alkylthio; and Y is OH, itsoptically active substance, their pharmaceutically acceptable salt, orhydrate thereof.
 5. A method for treating glomerulopathy which comprisesadministering an effective amount of a compound of the formula (XI) anda pharmaceutically acceptable carrier:

wherein R¹ and Y are as defined in claim 1, R¹⁰ is hydrogen atom,optionally substituted lower alkyloxy, lower alkylthio, halogen,optionally substituted amino, optionally substituted lower alkyl, oroptionally substituted non-aromatic heterocyclic group; and R⁴ ishydrogen atom or lower alkyl; its optically active substance, theirpharmaceutically acceptable salt, or hydrate thereof.
 6. A method fortreating glomerulopathy which comprises administering an effectiveamount of a compound of the formula (XII) and a pharmaceuticallyacceptable carrier:

wherein R¹ and Y are as defined in claim 1, R¹² is hydrogen atom,halogen, nitro, optionally substituted lower alkyl, lower alkyloxy, orlower alkylthio; and R¹⁴ is hydrogen atom or lower alkyl; its opticallyactive substance, their pharmaceutically acceptable salt, or hydratethereof.
 7. The method for treating glomerulopathy of claim 1, whereinR¹ is methyl, i-propyl, i-butyl or benzyl.
 8. The method for treatingglomerulopathy of claim 1, wherein R¹ is i-propyl or benzyl.
 9. Themethod for treating glomerulopathy of claim 1, wherein theglomerulopathy is glomerulonephritis.
 10. The method for treatingglomerulopathy of claim 1, wherein the glomerulopathy is diabeticnephropathy.
 11. The method for treating glomerulopathy of claim 1,wherein R² is hydrogen atom.